Ophthalmic composition



United States Patent 3,374,144 OPHTHALMIC COMPOSITION Morris Emmanuel Stolar, Parsippany, N.J., assignor to Miles Laboratories, Inc., Elkhart, Ind., a corporation of Indiana No Drawing. Filed Oct. 7, 1965, Ser. No. 493,931 3 Claims. (Cl. 167-59) The present invention relates to ophthalmic solutions. In one of its more particular aspects it relates to stabilized aqueous compositions of certain local anesthetics and fluorescein salts. In another aspect it realtes to aqueous solutions of normally insoluble reaction products of such local anesthetics and fluorescein compounds and to a process for forming such solutions.

In the examination and treatment of the eye by practitioners in the art, it is customary practice to employ a local anesthetic to reduce to a minimum the pain encountered by the patient in this sensitive area. It is also customary and extremely valuable in certain types of examinations of the cornea and duct systems of the eye to employ a stain; For example, this stain is necessary to determine if the cornea has become denuded as a result of laceration or ulceration. The stain may also be employed to determine if the duct systems between the nose and eyes are open. In this matter it has been usual practice to utilize a' solution of a local anesthetic followed by a separate staining solution to accomplish these tests, This separation of solutions has been necessary because of the reaction between the water soluble form of local anesthetics and the stain, which reaction often results in the formation of an insoluble precipitate. Needless to say, a liquid ophthalmic preparation containing an insoluble reaction product is unacceptable to the art both from the standpoint of lacking elegance as well as for technical and physiological reasons.

It is therefore an object of the present invention to provide a stain having anesthetizing properties for ophthalmic -use. It is another object to provide a process for solubilizing certain local anesthetic-fiuorescein stain adducts or reaction products. These and other objects will become apparent from the ensuing disclosure and the claims ap- I pended thereto.

"ing effects and yet suffer none of the aforementioned drawbacks.

The local anesthetics of the present invention are generally water soluble compounds and may be defined generically by the formula:

where Ar is an aromatic radical and may be a phenyl ..radical or a phenyl radical substituted with alkyl groups,

ice

alkoxy groups, amino groups, alkylamino groups, or various combinations thereof; X is -O Lldocalne hydrochloride (2-diethylamlno-2',6 acetoxylidide Tetracalne hydrochloride (2-dimethylamlnoethyl-p-nbutylaminobenzoate hydrochloride) Proparacaine hydrochloride (2 diethylaminoethyl-3-amlno- 4-npropoxybenzoate hydrochloride) I NH:

'I'ICl Cal-I5 Procaine hydrochloride (2-diethylaxninoethyl-p-amlnobenzoate hydrochloride) Benoxinate hydrochloride (2-diethylaminoethyl-4-amluo- 3-n-butoxybenzoate hydrochloride) CzHs Piperocaine hydrochloride (racemlc-v-(Eniethylplperldyl) propylbenzoate hydrochloride CH: a t C v -doornon,rv v 1101 The stain of the present invention, which is utilized, for example, to define the diseased or abraded areas of the cornea, or to detect foreign objects therein, may be described generally as an alkali metal water soluble fluorescein salt, an illustrative example of which is sodium fl-uorescein.

As noted, the result of combining two water soluble constituents such as lidocaine hydrochloride and sodium fluoresceinis the formation of the water insoluble adduct, lidocaine fiuoresceinate. This is demonstrated as follows:

about 0.25% by weight of an alkali metal fluorescein salt.

It has now been found that normally insoluble adducts such as lidocaine fluoresceinate can be solubilized by the utilization of certain alkoxylated fatty substances. In this respect, a water soluble alkoxylated lanolin fraction has been found to be a preferable solubilizing agent. These water soluble alkoxylated lanolin fractions can be prepared by utilizing alkoxylation processes on lanolin fractions having certain physical properties as will be elucidated hereinafter.

Lanolin, also known as wool fat, is a complex, tenacious, fat-like material obtained from the wool of sheep. It contains esters of fatty acids in combination with certain steroid compounds. For purposes of the present invention, the term fatty substance will be used to define a material such as lanolin as well as other fatty acids, fatty alcohols and various other complex mixtures which include fatty materials.

Lanolin can be fractioned into various cuts, such as by the process outlined in US. Patent No. 2,758,125 to C. J. Stunde. This patent teaches the production of a cut or fraction of lanolin having a cloud point of up to about 70 F. The cloud point of a particular liquid material is that temperature at which certain constituents begin to separate from a clear solution or admixture of ingredients in liquid form. In the instant situation, it is preferable to employ a fraction separated from lanolin in which, when the temperature thereof is lowered to 70 F., or lower, certain ingredients of this fraction begin to separate from the clear liquid. This water insoluble lanolin fraction having the cloud point of up to about 70 F. is then alkoxylated to form a liquid, water soluble lanolin. It has been found preferable to utilize the ethoxylated lanolin fraction as the solubilizing agent in the present invention.

Ususally the Water soluble lanolin fraction is suflicient in itself as a solubilizing agent in the practice of the present invention. However, it has been found that for long term stability it is preferable to include a small amount of a surface active agent such as polyoxyethylene sorbitan monooleate, in order to keep certain constituents of the lanolin fraction in solution.

The ophthalmic solutions of the present invention can be prepared by combining from about 0.125% to about 1.0% by weight of local anesthetic and an equimolar amount of fluorescein dye to form the adduct utilized in the present invention. The preferable quantities of such ingredients are from about 0.25% to about 0.50% by weight of local anesthetic and from about 0.125% to Lidocaine Fluoresceinate The amount of solublizing agent, of course, is dependent upon the amount of active ingredients utilized in the soltuion. In this respect it has been found that from about 0.5% to about 5.0% by weight of water soluble lanolin fraction and an equal amount of surfactant, if such is desired and necessary, is sufficient to solubilize the local anesthetic-fluorescein salt adduct. The amount of solubilizing agent used is proportional to the amount of active ingredients present.

It is known in the art that the local anesthetics differ in potency, onset of action and duration. The selection of the particular anesthetic must therefore be determined according to the need. For example, if anesthesia is desired quickly and need last for only a short period of time, a compound such as tetracaine-hydrochloride is the preferred material. On the other hand if a longer acting anesthetic is needed, lidocaine hydrochloride is such a preferable compound. It is within the contemplation of the present invention that various mixtures of local anesthetics may also be employed to achieve a certain anesthetic effect. In this respect it may be that a local anesthetic of short duration and rapid onset be combined with a local anesthetic of more prolonged duration, thus achieving the desired effect of rapid onset and prolonged duration.

It has been found that for general ophthalmic applications compositions of the present invention utilizing an adduct of tetracaine hydrochloride and sodium fluorescein are preferred. This combination has the advantage of producing an anesthesia of rather short duration which, for safety reasons, is quite desirable in the more common eye examinations and treatments. If the anesthesia were to persist longer, the patient might be in danger of eye damage from air-borne foreign particles, which because of the anesthesia produced, would not be ejected by the normal eye reflexes.

Various adjuvants, as needed, can also be included in the present composition. In this regard such materials as preservatives, buffers, salts to form isotonic solutions, and so forth, can be advantageously utilized. The composition should have a pH Within the range of from about pH 4.0 to pH 7.5. In this respect it has been found that for stability reasons a pH range of from about pH 4.0 to pH 5.5 is preferable for tetracaine fluoresceinate. The pH of the solution can be adjusted by the use of conventional buffers such as citrate-phosphate buffer.

In preparing the compositions of the present invention, either the free base form or the water soluble halide salt of the local anesthetic can be used. If the free base is used, its is necessary to first dissolve the base in an acidic solution. The fiuorescein salt is then added in a solution containing the solubilizing agent. Although this mode of preparation is preferable and has the advantage of forming the solubilized adduct in situ, the composition can also be prepared by first forming the adduct and subsequently solubilizing the adduct with the solubilizing agents of the present invention. Other adjuvants or pH adjustment additives may be added after the formation of the solution containing the adduct.

The following examples are merely illustrative of the practice of the present invention and are not intended to be any limitation of the inventive concept as disclosed herein.

Example 1 One (1.0) gram of a water soluble ethoxylated lanolin fraction (Lantrol AWS) and 1.0 gram of polyoxyethylene sorbitan monooleate were dissolved in 50 ml. of sterile water. One half (05) gram of tetracaine hydrochloride and 0.25 gram of sodium fluorescein were then dissolved in the solution, after which 0.8 gram of sodium chloride was added to make the solution isotonic. The pH of the solution was then adjusted to 5.1 by means of a citric aciddibasic sodium phosphate bufier solution, and finally the volume of the solution was adjusted to 100ml. by the addition of sterile water. The resultant ophthalmic solution was a clear tetracaine fluoresceinate composition which was found to be useful in anesthetizing the eye and defining denuded portions thereof.

Example 2 In a sterile vessel, 0.5 gram of lidocaine free base was dissolved in 50 ml. of sterile water containing 0.2 ml. of concentrated hydrochloric acid. In another sterile vessel 0.25 gram of sodium fiuorescein was dissolved in 30 ml. of sterile water containing 0.75 gram of a water soluble ethoxylated lanolin fraction (Lantrol AWS). The two solutions were then combined and the volume of the solution adjusted to 100 ml. with distilled water. The pH of the solution was determined to be 6.8. The result was a clear, lidocaine fluoresceinate ophthalmic solution useful in anesthetizing and staining the eye.

In summary, the present invention provides a novel ophthalmic solution of an adduct of a local anesthetic and a fluorescein stain. This solution, which would normally be unstable and an insoluble reaction product, is stabilized by the presence therein of an alkoxylated fatty substance. The resultant single clear solution exhibits both anesthetic and staining characteristics which greatly facilitates ophthalmological examinations.

What is claimed is:

1. An ophthalmic composition which comprises an aqueous solution of from about 0.125% to about 1.0% by weight of a local anesthetic selected from the group consisting of lidocaine, tetracaine, procaine, proparacaine, benoxinate and piperocaine and an equirnolar amount of sodium fluorescein, and from about 0.5 to about 5.0% by weight of water soluble liquid ethoxylated lanolin and from 0.5% to about 5.0% of polyoxyethylene sorbitan monooleate.

2. A composition as in claim 1 wherein the local anesthetic is tetracaine hydrochloride.

3. A composition as in claim 1 wherein the local anesthetic is tetracaine and which additionally comprises a buffer for maintaining the composition at a pH of from about 4.0 to about 5.5.

References Cited UNITED STATES PATENTS 3,171,752 3/1965 Rankin 16759 OTHER REFERENCES Barnett: Drug and Cosmetic Industry, June 1957, vol. 80, No. 6, pp. 745 and 845.

Vincent et 'al.: Journal of the American Pharmaceutical Association, vol. 20, No. 2, February 1959, pp. 83-85.

Fenton, Brit. J.: Ophthal, vol. 48, p. 633, November 1964. Physicians Desk Reference, Medical Economics, Inc., Oradell, New Jersey, 16th ed., 1962, p. 587.

Martin; Husas Pharmaceutical Dispensing, 5th ed., Mack Publishing Co., Easton, Pa., 1959, pp. 263-266.

ALBERT T. MEY ERS, Primary Examiner.

SAM ROSEN, Examiner.

J. D. GOLDBERG, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,374,l44 March 19 1968 Morris Emmanuel Stolar It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 13, "realtes" should read relates Column 3, lines 14 to 28, the formula should appear as shown below:

2 S 2 l i O C-CH -I i1 O H C CH C H 2 5 2 H3 663 L H l C O i 2 N +2N3Cl Signed and sealed this 16th day of September 1969. V

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents 

1. AN OPHTHALMIC COMPOSITION WHICH COMPRISES AN AQUEOUS SOLUTION OF FROM ABOUT 0.125% TO ABOUT 1.0% BY WEIGHT OF A LOCAL ANESTHETIC SELECTED FROM THE GROUP CONSISTING OF LIDOCAINE, TETRACAINE, PROCAINE, PROPARACAINE, BENOXINATE AND PIPEROCAINE AND AN EQUIMOLAR AMOUNT OF SODIUM FLUORESCEIN, AND FROM ABOUT 0.5% TO ABOUT 5.0% BY WEIGHT OF WATER SOLUBLE LIQUID ETHOXYLATED LANOLIN AND FROM 0.5% TO ABOUT 5.0% OF POLYOXYETHYLENE SORBITAN MONOOLEATE. 